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Abstract Depression is associated with dysregulated circadian rhythms, but the role of intrinsic clocks in mood-controlling brain regions remains poorly understood. We found increased circadian negative loop and decreased positive clock regulators expression in the medial prefrontal cortex (mPFC) of a mouse model of depression, and a subsequent clock countermodulation by the rapid antidepressant ketamine. Selective Bmal1KO in CaMK2a excitatory neurons revealed that the functional mPFC clock is an essential factor for the development of a depression-like phenotype and ketamine effects. Per2 silencing in mPFC produced antidepressant-like effects, while REV-ERB agonism enhanced the depression-like phenotype and suppressed ketamine action. Pharmacological potentiation of clock positive modulator ROR elicited antidepressant-like effects, upregulating plasticity protein Homer1a, synaptic AMPA receptors expression and plasticity-related slow wave activity specifically in the mPFC. Our data demonstrate a critical role for mPFC molecular clock in regulating depression-like behavior and the therapeutic potential of clock pharmacological manipulations influencing glutamatergic-dependent plasticity.

Abstract While depression and chronic pain are frequently comorbid, underlying neuronal circuits and their psychopathological relevance remain poorly defined. Here we show in mice that hyperactivity of the neuronal pathway linking the basolateral amygdala to the anterior cingulate cortex is essential for chronic pain-induced depression. Moreover, activation of this pathway in naive male mice, in the absence of on-going pain, is sufficient to trigger depressive-like behaviors, as well as transcriptomic alterations that recapitulate core molecular features of depression in the human brain. These alterations notably impact gene modules related to myelination and the oligodendrocyte lineage. Among these, we show that Sema4a, which was significantly upregulated in both male mice and humans in the context of altered mood, is necessary for the emergence of emotional dysfunction. Overall, these results place the amygdalo-cingulate pathway at the core of pain and depression comorbidity, and unravel the role of Sema4a and impaired myelination in mood control.